HIV AND HCV DISEASE PROGRESSION IN WOMEN ON HAART

描述(申请人提供)：艾滋病毒感染引起广泛的全球免疫激活，涉及免疫系统的先天和适应性手臂，增加了艾滋病和艾滋病毒相关的非艾滋病条件(HANA)，即使成功地进行了HAART治疗。我们的研究表明，高水平的免疫激活和衰老在艾滋病毒疾病的早期出现，并与艾滋病、心血管和肝脏疾病的发生有关，特别是在合并感染丙型肝炎的妇女中。这次更新的总体目标是继续研究这种免疫过度激活状态的机制和后果及其对加速疾病的影响。我们将评估异常细胞因子产生的后果，这些细胞因子可能促进纤维化形成或组织损伤，并改变T细胞的成熟、调节和免疫功能。我们发现，合并感染肝纤维化的女性调节性T细胞明显减少，衰老、终末分化和效应记忆T细胞的百分比增加，这表明免疫失调可能会加速炎症反应，最终导致器官疾病。在这项建议中，我们将全面调查长期激活和免疫失调对WIHS中具有良好特征的女性队列的临床结果的影响。利用多参数流式细胞术、实时聚合酶链式反应和聚合酶链式反应芯片技术，我们开发了系统地评估影响疾病的免疫学和病毒学因素的平台。我们进行了复杂的验证实验，允许同时评估可溶性和细胞生物标记物，免疫激活、衰竭、衰老和调节的分子基因签名，以及来自一个样本的病毒学研究。我们的中心假设是，HIV相关的免疫失调和合并肝功能障碍的丙型肝炎病毒感染维持这种免疫过度激活状态，导致免疫衰竭和衰老，即使使用有效的HAART，HANA条件也会更快地进展。此外，肝脏疾病将在决定免疫学、病毒学和临床结果方面发挥重要作用，特别是在妇女进入更年期和年龄的时候。我们的具体目标是：1)确定成功接受HAART治疗的单独和联合感染妇女长期免疫激活的决定因素和后果；2)评估促进免疫激活、衰老、衰竭和进展为临床结果的分子机制中涉及的基因表达模式。对于特定的目标1，我们将纵向比较细胞因子和激活和免疫调节的可溶性和细胞标记物的水平，并确定对免疫衰老/衰竭和疾病结局的影响。针对特定目标2，我们将使用实时定量PCR阵列技术评估免疫的固有宿主基因特征信号通路，并将评估与免疫激活、衰竭和衰老相关的干扰素反应。这些研究将确定长期激活和调节失调对衰老和精疲力竭的影响，以及丙型肝炎病毒合并感染的作用，希望开发出可能防止持续过度激活和发病的治疗策略。

DESCRIPTION (provided by applicant): HIV infection causes generalized global immune activation involving both the innate and adaptive arms of the immune system increasing AIDS and HIV-related non-AIDS conditions (HANA), even with successful HAART treatment. Our studies demonstrate that high levels of immune activation and senescence are seen early in HIV disease and are associated with incident AIDS, cardiovascular and liver disease especially in HCV co- infected women. The overall goal of this renewal is to continue examining mechanisms and consequences of this immune hyperactivation state and its impact on accelerated disease. We will evaluate the consequences of aberrant cytokine production that may promote fibrogenesis or tissue damage and alter T cell maturation, regulation and immune function. We find that co-infected women with liver fibrosis have significantly fewer regulatory T cells and increased percentage of senescent and terminally differentiated and effector memory T cells, indicating that immune dysregulation may accelerate "inflammaging" and end organ disease. In this proposal, we will comprehensively investigate the effect of long-term activation and immune dysregulation on clinical outcome in a well characterized cohort of women in WIHS. Using multiparameter flow cytometry, real- time PCR and PCR array technologies, we developed platforms to systematically evaluate both immunologic and virologic factors impacting disease. We performed complex validation experiments allowing simultaneous evaluation of soluble and cellular biomarkers, molecular gene-signatures of immune activation, exhaustion, senescence and regulation, and virologic studies from one sample. Our central hypothesis is that HIV- associated immune dysregulation and HCV infection with liver dysfunction maintains this state of immune hyperactivation, leading to immune exhaustion and senescence and more rapid progression of HANA conditions, even with effective HAART. Furthermore, liver disease will play a major role in determining immunologic, virologic and clinical outcomes especially as women age and enter menopause. Our specific aims are: Specific Aim 1) Define determinants and consequences of long-term immune activation in singly and co-infected women successfully treated with HAART and Specific Aim 2) Assess gene expression patterns involved in molecular mechanisms promoting immune activation, senescence, exhaustion, and progression to clinical outcomes. For Specific Aim 1, we will longitudinally compare levels of cytokines and soluble and cellular markers of activation and immune regulation and determine impact on immune senescence/exhaustion and disease outcome. For Specific Aim 2, we will evaluate intrinsic host gene- signature pathways of immunity using real time PCR array technology and will evaluate interferon response related to immune activation, exhaustion and senescence. These studies will identify the impact of long-term activation and dysregulation on senescence and exhaustion and the role of HCV co-infection in hopes of developing treatment strategies that may prevent continued hyperactivation and the onset disease.